AU702141B2

AU702141B2 - Process for preparing enantiomerically pure tropic acid esters

Info

Publication number: AU702141B2
Application number: AU58120/96A
Authority: AU
Inventors: Rolf Banholzer
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1995-04-28
Filing date: 1996-04-29
Publication date: 1999-02-11
Anticipated expiration: 2016-04-29
Also published as: NO974967L; CZ292579B6; BG101948A; SK144497A3; ATE208389T1; CN1183098A; NO316175B1; DE19515625A1; JP3988056B2; HK1010878A1; US5952505A; KR100386383B1; SK283793B6; BR9608288A; CZ340597A3; EP0822935B1; RO118871B1; HUP9802210A2; CN1050357C; WO1996033996A1

Abstract

PCT No. PCT/EP96/01779 Sec. 371 Date Nov. 19, 1997 Sec. 102(e) Date Nov. 19, 1997 PCT Filed Apr. 26, 1996 PCT Pub. No. WO96/33996 PCT Pub. Date Oct. 31, 1996Precursors of anticholinergically active quaternary compounds can be synthesized from optically active tropic acid by acetylation, conversion into the acid chloride, reaction with amino alcohols of formula (I) (as the methanesulphonate; Q and R are explained in the specification), deacetylation and isolation of the reaction product.

Description

2 It has now been found that enantiomerically pure and (-)-tropic acid esters of amino alcohols of formula

II,

HO

(II)

wherein Q denotes CH2-CH 2

CH

2

-CH

2 CH=CH or CH CH, 0 R denotes a straight-chained or branched

CI-

4 -alkyl group, ~eS r can surprisingly be prepared by 25 o acetylating the corresponding optically active -tropic acid (HOCH2-

*HCOOH),

converting the resulting O-acetyl tropic acid with thionyl chloride into the acid chloride, reacting the latter at ambient temperature in an inert solvent, optionally with the addition of excess aluminium oxide, with the methanesulphonate of an amino alcohol of formula

I,

wherein R and Q are as defined above deacetylating the resulting compound by the action of a strong acid,and 3 isolating the optically active tropic acid ester obtained.

The and (-)-tropic acid required as starting material can be obtained from D,L-tropic acid by first preparing a salt with an optically active base in a manner known per se and recrystallising this salt several times. A suitable base might be, for example, (-)-quinine whilst the solvent for crystallisation might be ethanol. The (+)-tropic acid thus prepared has a purity of 99.8% 20 +73.1; c 1 in ethanol).

D

The reaction according to is preferably carried out at ambient temperature and the reaction according to (b) which is carried out immediately afterwards is preferably performed without intermediate isolation of the acetylated acid at ambient temperature or slightly elevated temperature.

Step takes place within a few days, when the methanesulphonate of a compound of formula is reacted in an inert solvent, such as methylene chloride, at temperatures between 0°C and about 30 0 C, preferably at ambient temperature, with stirring, whilst excess aluminium oxide may be used to bind the acid. Once the solvent has been eliminated under reduced pressure, the residue can be further processed directly.

In step favourable results are obtained if the deacetylation is carried out with a dilute aqueous inorganic acid, such as 2 20% hydrochloric acid, preferably 3 10% hydrochloric acid, at ambient temperature. Thus, for example, total reaction is obtained with 5% hydrochloric acid within about 2 days.

The reaction product can be isolated as a base (step by stirring the acidic reaction solution into 4 excess dilute 20%) sodium hydroxide solution or into aqueous alkali metal carbonate solution and filtering off the crystalline product precipitated.

Temperatures of between -15 and +50 0 C may be used; it is preferable to use sodium carbonate solution at about 0 C. The salts, e.g. the corresponding hydrochloride, can easily be prepared from the base by adding a stoichometric quantity of ethereal hydrochloric acid to the solution of the base, e.g. in methylene chloride.

The esters obtained in this way consist of more than 99% of the pure optically active compound, assuming that the starting acid is correspondingly pure.

The optically active esters which may be obtained according to the invention are valuable intermediate products for producing the corresponding anticholinergic quaternary compounds, such as the corresponding methobromides or methomethanesulphonates, which may be used, for example, as agents for treating asthmatic diseases or obstructive diseases of the respiratory tract.

The quaternary compounds may be prepared by conventional methods without racemisation.

The reaction according to the invention is explained more fully in the Examples which follow, but the reaction conditions according to the invention are not limited to the specific data provided.

5 Example 1 (-)-Tropic acid-N-isopropylnortropine ester hydrochloride 13.3 g of (-)-Tropic acid are added to 31.4 g of acetyl chloride with stirring and at ambient temperature and within one hour a clear solution is formed. After another hour, the reaction is virtually complete, according to thin layer chromatography (TLC). 47.5 g of thionyl chloride are added dropwise to the (-)-O-acetyl tropic acid solution over 30 minutes. The solution is stirred overnight at ambient temperature, then for a further hour at 50 0 C. After evaporation at 35 0 C under reduced pressure, 18.9 g of a brownish liquid remain, [a]20= -87.8 (c 0.5 in chloroform). The presence of

D

the desired compound can be confirmed by spectroscopy.

7.26 g (0.0275 mol) of N-isopropylnortropine methanesulphonate and 6.20 g (0.0275 mol) of the product obtained in are stirred in 45 ml of methylene chloride at ambient temperature. After seven days the reaction solution is evaporated down under reduced pressure at 30 0 C. The residue (16.9 g) is used for the next step without being further worked up.

11.1 g of the product according to are dissolved in 60 ml of 5% hydrochloric acid and stirred for 2 days at ambient temperature. TLC indicates quantitative deacetylation.

The reaction solution is extracted twice with a little diethylether, then any residual ether is eliminated under reduced pressure. Excess 20% aqueous sodium carbonate solution is then stirred into the solution, and a crystalline product is precipitated. It is filtered off and washed with cold water until the filtrate running away shows only a slightly alkaline reaction, and is then dissolved in methylene chloride.

6 After drying over sodium sulphate, the solvent is distilled off under reduced pressure and the residue is recrystallised from acetonitrile. White crystals are obtained, m.p. 131 0 C, [a] 20 -19.1 (c=1 in ethanol).

D

In order to prepare the hydrochloride, the solution of the base in methylene chloride is combined with the stoichiometric amount of ethereal hydrochloric acid.

After the product has been recrystallised from ethanol and acetonitrile, the (-)-tropic acid-N-isopropylnortropine ester hydrochloride is obtained in the form of white crystals, m.p. 214-8 0

C.

-27.8 (c=l in water); optical purity >99.8%.

The presence of the compound was confirmed by elemental analysis and spectroscopy.

Quaternisation to obtain the methobromide is carried out, for example, by reacting with methyl bromide in methylene chloride/acetonitrile at ambient temperature.

White crystals are obtained (yield 75.2% of theory, m.p.

20 238-42°C with decomposition).

[]20 -24.5 (c 1 in water); optical purity >99.5%.

9.

25 Example (+)-Tropic acid-N-isopropylnortropine esterhydrochloride Starting from (+)-tropic acid, which may be obtained by racemate cleaving from D,L-tropic acid with (-)-quinine, +73.1 (c 1 in ethanol; optical purity 99.8%), the title compound is obtained analogously to Example 1 in the form of white crystals, m.p. 214-7 0 C, with decomposition, [a]2 0 +27.8 (c 1 in water). Yield 55.7% of theory. Once again, the presence of the compound is confirmed by elemental analysis and spectroscopy.

7 As described in Example 1; the compound obtained is reacted to form the methobromide; m.p. 238-41 0

C

(decomp.), [a] 2 0 +25.3 (c 1 in water).

D

For reacting the O-acetyltropic acid chlorides with the compounds yields of between 60 and 70% are obtained if the reactions continue at room temperature for several days, and in addition to methylene chloride, for example, dimethylformamide or acetonitrile as reaction medium will give similar results.

8 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: i. Process for preparing enantiomerically pure and (-)-tropic acid esters of amino alcohols of formula

II,

100 HO 0

(II)

wherein Q denotes

CH

2 -CH2,

CH

2

-CH

2

-CH

2 CH=CH or CH -CH, 0 *i R denotes a straight-chained or branched Cx.

4 -alkyl 20 group, characterised in that the corresponding optically active tropic acid is 25 acetylated, the resulting O-acetyltropic acid is converted with thionyl chloride into the acid chloride, the latter is reacted at ambient temperature in an inert solvent with the methanesulphonate of an amino alcohol of formula HO R-N

(I)

wherein R and Q are as defined above wherein R and Q are as defined above deacetylating the resulting compound by the action of a strong acid,and

Claims

9- the resulting optically active tropic acid ester is isolated. 2. Process according to claim 1 characterised in that the reaction is carried out in the presence of excess aluminium oxide. 3. Process according to claim 1 characterised in that the optically active tropic acid ester is precipitated from the acid solution using aqueous sodium carbonate solution. 4. Process according to claims 1 to 3, characterised S in that N-isopropylnortropine methanesulphonate is used as the compound of formula 5. Process according to any one of claims 1 to 4 substantially as hereinbefore described with reference to the Examples. •go 10 Precursors of anticholinergically active quaternary compounds can be synthesised from optically active tropic acid by acetylation, conversion into the acid chloride, reaction with amino alcohols of formula (I) H-O- R-N (I) (as the methanesulphonate; Q and R are explained in the specification), deacetylation and isolation of the reaction product.